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ABSTRACT: Objectives: This study aimed to evaluate the molecular epidemiology and antimicrobial resistance of invasive pneumococcal isolates from children in Shenzhen, China, in the early stage of the pneumococcal 13-valent conjugated vaccine (PCV-13) era from 2018 to 2020. Methods: Invasive pneumococcal strains were isolated from hospitalized children with invasive pneumococcal diseases (IPDs) from January 2018 to December 2020. The serotype identification, multilocus sequence typing (MLST), and antibiotic susceptibility tests were performed on all culture-confirmed strains. Results: Sixty-four invasive strains were isolated mainly from blood (70.3%). Prevalent serotypes were 23F (28.1%), 14 (18.8%), 19F (15.6%), 6A/B (14.1%), and 19A (12.5%), with a serotype coverage rate of 96.9% for PCV13. The most common sequence types (STs) were ST876 (17.1%), ST271 (10.9%), and ST320 (7.8%). Half of the strains were grouped in clonal complexes (CCs): CC271 (21.9%), CC876 (20.3%), and CC90 (14.1%). Meningitis isolates showed a higher resistance rate (90.9% and 45.5%) to penicillin and ceftriaxone than the rate (3.8% and 9.4%) of non-meningitis isolates. The resistance rates for penicillin (oral), cefuroxime, and erythromycin were 53.13%, 73.4%, and 96.9%, respectively. The dual ermB and mefA genotype was found in 81.3% of erythromycin-resistant strains. The elevated minimum inhibitory concentration (MIC) of β-lactam antibiotics and dual-genotype macrolide resistance were related mainly to three major serotype-CC combinations: 19F-CC271, 19A-CC271, and 14-CC876. Conclusion: Invasive pneumococcus with elevated MICs of β-lactams and increased dual ermB and mefA genotype macrolide resistance were alarming. Expanded PCV13 vaccination is expected to reduce the burden of paediatric IPD and to combat antibiotic-resistant pneumococcus in Shenzhen.

Objectives: We characterized the population structure and features of clinical Streptococcus pneumoniae isolates associated with invasive pneumococcal disease (IPD) from 2009 to 2017 in a Chinese metropolitan city using a whole-genome sequencing approach. Methods: Seventy-nine pneumococcal strains, including 60 serogroup-19 strains from children enduring IPD from a paediatric hospital in Shenzhen, were subjected to whole-genome sequencing. Population structure was characterized through phylogenetic analysis, sequence typing, serotyping, virulence factor, and antimicrobial drug resistance (AMR) gene profiling, combining the publicly available related WGS data. Clinical demography and antibiotic susceptibility profiles were compared among different populations to emphasize the higher-risk populations. Genetic regions associated with AMR gene mobilization were identified through comparative genomics. Results: These IPD strains mainly belonged to clonal complex 320 (CC320) and were composed of serotypes 19A and 19F. In addition to sporadic possible importation-related isolates (ST320), we identified an independent clade, CC320_SZpop (ST271), that predominantly circulated in Shenzhen and possibly expanded its range. Clinical features and antibiotic susceptibility analysis revealed that CC320_SZpop might manifest much higher pathogenicity and tolerance to β-lactams. Specific virulence factors in Shenzhen isolates of CC320_SZpop were identified. Furthermore, an ca. 40 kb hotspot genomic region enduring frequent recombination was identified, possibly associated with the divergence of S. pneumoniae strains. Conclusion: A novel pneumococcal clade, CC320_SZpop, circulating in Shenzhen and other regions in China, possibly under expansion, was found and deserves more study and surveillance. Our study also emphasizes the importance of continuous genomic surveillance of clinical S. pneumoniae isolates, especially IPD isolates.

Streptococcus is one of the common pathogens of suppurative infections. Invasive group A Streptococcus (iGAS) infections often develop from skin or soft tissue infections, and streptococcal toxic shock syndrome is considered the main cause of death in Chinese children with iGAS infectious disease. However, soft tissue infections caused by iGAS infections, especially the formation of abscesses, are relatively rare. A retrospective study was conducted, and pediatric in-patients who were diagnosed with an iGAS infection identified by cultures from normally sterile sites and treated in a tertiary hospital during 2016–2018 were included. A total of 14 patients were identified, which included 10 boys and four girls. The patients had an age range from 3 months to 10 years and were diagnosed with soft tissue infections and a formation of abscesses caused by iGAS infections. The most common sites of infections were the lower limbs. In five patients, the abscess was accompanied by fever, and the local soft tissue showed redness, swelling, tenderness, and an elevated skin temperature. Laboratory findings included an increased white blood cell (WBC) count in 12 patients, an increased C reactive protein (CRP) level in seven patients, and an increased erythrocyte sedimentation rate (ESR) in 10 patients. No patients had an elevated procalcitonin level. For all 14 patients, we performed puncture and drainage of abscesses, and cultured GAS from the drainage fluid. All children also received antibiotic treatment. During 2 months of follow-up, the patients' condition remained stable and no evidence of kidney or heart damage was observed. For pediatric patients with abscesses, early diagnosis, prompt treatment with incision and drainage, and immediate culture of the drainage fluid are important. Upon confirmation of an iGAS infection, β-lactam antibiotics should be given to provide effective treatment, and in some patients with poor therapeutic outcomes, the use of vancomycin as an alternative can achieve the desired results.

Abstract Objectives In this study, we describe the patterns of antibiotic prescription for neonates based on World Health Organization’s (WHO) Essential Medicines List Access, Watch, and Reserve (AWaRe), and the Management of Antibiotic Classification (MAC) Guidelines in China. Methods One-day point-prevalence surveys (PPS) on antimicrobial prescriptions were conducted on behalf of hospitalized neonates in China from September 1 and November 30, annually from 2017 to 2019. Results Data was collected for a total of 2674 neonatal patients from 15 hospitals in 9 provinces across China of which 1520 were newborns who received at least one antibiotic agent. A total of 1943 antibiotic prescriptions were included in the analysis. The most commonly prescribed antibiotic was meropenem (11.8%). The most common reason for prescribing antibiotic to neonates was pneumonia (44.2%). There were 419 (21.6%), 1343 (69.1%) and 6 (0.3%) antibiotic prescriptions in the Access, Watch and Reserve groups, respectively. According to MAC Guidelines in China, there were 1090 (56.1%) antibiotic agents in the Restricted and 414 (21.3%) in the Special group. Conclusion Broad-spectrum antibiotics included in the Watch and Special groups were likely to be overused in Chinese neonates.

BackgroundPCV13 introduction in China has led to a significant reduction of vaccine serotype Streptococcus pneumoniae. However, non-vaccine serotypes with highly resistance and invasiveness were often reported in the post-pneumococcal conjugate vaccine era and there was regional differences.MethodsA total of 669 S. pneumoniae strains were collected from the respiratory tracts of hospitalized children at Shenzhen Children’s Hospital in 2021 and 2022. Antimicrobial resistance (AMR) characteristics were assessed through antibiotic susceptibility testing performed with the VITEK 2 compact system. AMR genes and single nucleotide polymorphisms (SNPs) in pbp1a, pbp2b, and pbp2x were identified via analysis of whole genome sequencing data. Statistical examination of the data was conducted employing chi-square and Fisher’s exact tests.ResultsWe found that non-vaccine serotypes strains had accounted for 46.6% of all the pneumococcal isolated strains. The most common non-vaccine serotype is 23A, with a prevalence rate of 8.9%, followed by 15A (6.6%), 6E (5.7%), 34 (3.2%), and 15B (2.9%). The multidrug resistance rates (MDR) of vaccine serotypes were 19F (99.36%), 19A (100%), 23F (98.08%), 6B (100%), and 6C (100%). Meanwhile, the MDR of non-vaccine serotypes were 15B (100.00%), 6E (100%), 15C (100%), 34 (95.24%), and 23A (98.31%). Resistance rates of 6E to more than six antibiotic classes reached 89.47%, which is similar to 19F (83.33%) and 19A (90%). Unique resistance profiles were also identified for non-vaccine serotypes, including significantly higher resistance to chloramphenicol in 6E, 15B, and 15C than in 19F and 19A. Furthermore, through genome sequencing, we revealed strong correlation of cat-TC with chloramphenicol resistance, patA/patB with tetracycline resistance, ermB and pmrA with erythromycin resistance.ConclusionThe introduction of PCV13 into China from 2017 has led to a shift in the dominant composition of pneumococcal strains. There has been a notable rise and spread of multidrug-resistant non-vaccine serotypes among children. Specifically, the non-vaccine serotype 6E, which was not widely reported in China previously, has emerged. To comprehend the resistance mechanisms, it is crucial to further investigate the molecular and genetic characteristics of these non-vaccine serotypes.

Abstract Background Respiratory symptoms are the earliest clinical manifestation of Talaromyces marneffei (TM) infection. In this study, we aimed to improve the early identification of TM infection in human immunodeficiency virus (HIV)-negative children with respiratory symptoms as the first manifestation, analyze the risk factors, and provide evidence for diagnosis and treatment. Methods We retrospectively analyzed six cases of HIV-negative children with respiratory system infection symptoms as the first presentation. Results All subjects (100%) had cough and hepatosplenomegaly, and five subjects (83.3%) had a fever; other symptoms and signs included lymph node enlargement, rash, rales, wheezing, hoarseness, hemoptysis, anemia, and thrush. Additionally, 66.7% of the cases had underlying diseases (three had malnutrition, one had severe combined immune deficiency [SCID]). The most common coinfecting pathogen was Pneumocystis jirovecii, which occurred in two cases (33.3%), followed by one case of Aspergillus sp. (16.6%). Furthermore, the value of β-D-glucan detection (G test) increased in 50% of the cases, while the proportion of NK decreased in six cases (100%). Five children (83.3%) were confirmed to have the pathogenic genetic mutations. Three children (50%) were treated with amphotericin B, voriconazole, and itraconazole, respectively; three children (50%) were treated with voriconazole and itraconazole. All children were tested for itraconazole and voriconazole plasma concentrations throughout antifungal therapy. Two cases (33.3%) relapsed after drug withdrawal within 1 year, and the average duration of antifungal treatment for all children was 17.7 months. Conclusion The first manifestation of TM infection in children is respiratory symptoms, which are nonspecific and easily misdiagnosed. When the effectiveness of anti-infection treatment is poor for recurrent respiratory tract infections, we must consider the condition with an opportunistic pathogen and attempt to identify the pathogen using various samples and detection methods to confirm the diagnosis. It is recommended the course for anti-TM disease be longer than one year for children with immune deficiency. Monitoring the blood concentration of antifungal drugs is important.

Abstract Background Nasopharyngeal swabs are taken to determine the causative agent of community acquired pneumonia (CAP), while the reliability of upper respiratory tract sampling as a proxy for lower respiratory tract infections is still unclear. Methods Nasopharyngeal (NP) swabs, bronchoalveolar lavage (BAL) fluid samples and clinical data were collected from 153 hospitalized children between 3 months and 14 years of age with severe CAP, enrolled from March to June 2019. Written informed consent for the storage and use of the samples for further studies was obtained from the parents or caregivers. Putative pathogens were detected using a sensitive, high-throughput GeXP-based multiplex PCR and qPCR. Results The same bacterial species in paired samples were found in 29 (23.4%) and the same viral species in 52 (27.5%) of the patients. moderate concordance was found for Mycoplasma pneumoniae (ĸ=0.64), followed by Haemophilus influenzae (ĸ=0.42). The strongest discordance was observed for human adenovirus and also for Pseudomonas aeruginosa, the latter was exclusively detected in BAL samples. In the adenovirus cases strong concordance was associated with high viral loads in the NP swabs. Conclusion The variation in concordance in pathogen detection in the upper and lower respiratory tract of children with severe pneumonia is generally high but varies depending on the species. Novel and impactful insights are the concordance between NP and BAL detection for M. pneumoniae and H. influenzae and the strong correlation between high adenoviral loads in NP swabs and detection in BAL fluid.

BackgroundTo summarize the clinical features of severe influenza in children and the high-risk factors for influenza-related deaths and to raise awareness among pediatricians.MethodsA retrospective study of clinical manifestations, laboratory tests, and diagnosis and treatment of 243 children with severe influenza admitted to Shenzhen Children's Hospital from January 2009 to December 2022 was conducted. Univariate logistic regression analysis and Boruta analysis were also performed to identify potentially critical clinical characteristics associated with death, and clinically significant were used in further multivariate logistic regression analysis. Subject receiver operating characteristic (ROC) curves were applied to assess the efficacy of death-related independent risk factors to predict death from severe influenza.ResultsThere were 169 male and 74 female patients with severe influenza, with a median age of 3 years and 2 months and 77.4% of patients under six. There were 46 cases (18.9%) in the death group. The most common pathogen was Influenza A virus (IAV) (81.5%). The most common complication in the death group was influenza-associated acute necrotizing encephalopathy (ANE [52.2%]). Severe influenza in children decreased significantly during the COVID-19 pandemic, with a median age of 5 years, a high predominance of neurological symptoms such as ANE (P = 0.001), and the most common pathogen being H3N2 (P

Abstract A range of public health measures have been implemented to suppress local transmission of coronavirus disease 2019 (COVID-19) in Shenzhen. We examined the effect of these measures on the prevalence of respiratory pathogens in children. Clinical and respiratory pathogen data were collected for routine care from hospitalized children with acute respiratory infections in Shenzhen Children’s Hospital from July 2018 to January 2022. Nasopharyngeal swabs were collected and respiratory pathogens were detected using standardized clinical diagnostics as part of routine care. Data were analyzed to describe the effects of COVID-19 prevention procedures on other common pathogens. A total of 56,325 children under 14 years of age were hospitalized with an acute respiratory infection during the study period, 33,909 were tested from July 2018 to January 2020 (pre-lockdown), 1168 from February 2020 to May 2020 (lockdown) and 21,248 from July 2020 to January 2022 (post-lockdown). We observed a 37.3% decline of routine care in respiratory infection associated hospital admission in the 19 months’ post-lockdown vs. the 19 months’ pre-lockdown. There were 99.4%, 16.0% and 1.26% reductions measured for Mycoplasma pneumoniae, influenza virus A and adenovirus, respectively. However, a 118.7% and 75.8% rise was found for respiratory syncytial virus (RSV) and human para-influenza virus (HPIV) during the 19 months’ post-lockdown in comparison to the pre-pandemic period. The detection of RSV especially increased in toddlers after the lockdown. Lockdown measures during the COVID-19 pandemic led to a significant reduction of Mycoplasma pneumoniae, influenza virus A and adenovirus infection. In contrast, RSV and HPIV infection increased.

IntroductionThe incidences of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), which were leading causes of death in children in the 1920s, have decreased substantially. Considering the recent resurgence of scarlet fever and increased incidence of streptococcal pharyngitis in children, an investigation of the current status of ARF and RHD may be worthwhile.ObjectiveTo summarize the prevalence trends, pathogenic factors, and prevention strategies for ARF and RHD in children.MethodsA selective search of literature published between January 1920 and February 2023 was done in PubMed, using the terms “acute rheumatic fever”, “rheumatic heart disease”, “group A Streptococcus”, “pharyngitis”, “pharyngeal tonsillitis”, “scarlet fever”, “impetigo”, “obstructive sleep apnea syndrome” and “child”.ResultsOvercrowded homes and inadequate sanitation led to recurrent group A streptococcal infection, and the causal relationship between group A streptococcal infection and ARF/RHD was well established. Streptococcal infectious diseases, such as group A streptococcal pharyngeal tonsillitis, SF, impetigo, and obstructive sleep apnea syndrome, were associated with the occurrence of ARF and RHD. ARF and RHD were still prevalent in young people of developing countries and economically poor populations of high-income countries. Universal disease registration systems were critical to locating disease outbreaks, tracking disease transmission, and identifying high-risk populations. Four-level prevention strategies were effective in reducing the incidence and mortality of ARF and RHD.ConclusionsRegistry and preventive measures for ARF and RHD should be strengthened in areas of dense population; poor sanitation; resurgence of SF; and high incidence of streptococcal pharyngitis, impetigo, and obstructive sleep apnea syndrome.

With the widespread use of antibiotics, antimicrobial resistance (AMR) has become a global problem that endangers public health. Despite the global high prevalence of group A Streptococcus (GAS) infections and the global widespread use of β-lactams, β-lactams remain the first-line treatment option for GAS infection. β-hemolytic streptococci maintain a persistent susceptibility to β-lactams, which is an extremely special phenomenon in the genus Streptococci, while the exact current mechanism is not known. In recent years, several studies have found that the gene encoding penicillin binding protein 2X (pbp2x) is associated with GAS with reduced-β-lactam susceptibility. The purpose of this review is to summarize the current published data on GAS penicillin binding proteins and β-lactam susceptibility, to explore the relationship between them, and to be alert to the emergence of GAS with reduced susceptibility to β-lactams.

Talaromyces marneffei and Pneumocystis jirovecii are the common opportunistic pathogens in immunodeficient patients. There have been no reports of T. marneffei and P. jirovecii coinfection in immunodeficient children. Signal transducer and activator of transcription 1 (STAT1) is a key transcription factor in immune responses. STAT1 mutations are predominately associated with chronic mucocutaneous candidiasis and invasive mycosis. We report a 1-year-2-month-old boy diagnosed with severe laryngitis and pneumonia caused by T. marneffei and P. jirovecii coinfection, which was confirmed by smear, culture, polymerase chain reaction and metagenome next-generation sequencing of bronchoalveolar lavage fluid. He has a known STAT1 mutation at amino acid 274 in the coiled-coil domain of STAT1 according to whole exome sequencing. Based on the pathogen results, itraconazole and trimethoprim-sulfamethoxazole were administered. This patient’s condition improved, and he was discharged after two weeks of targeted therapy. In the one-year follow-up, the boy remained symptom-free without recurrence.

To investigate the clinical characteristics and treatment of septic arthritis caused by Streptococcus pyogenes(S. pyogenes) in children, we retrospectively analyzed the clinical data, laboratory results, treatments and outcomes of three pediatric cases of septic arthritis caused by S. pyogenes occurring from 2016–2018. The three cases of septic arthritis included 1 boy and 2 girls, aged from 2–7 years. Two patients experienced fever, and in all three cases, the affected joints showed redness, swelling, an increased local skin temperature, tenderness and restricted limb movement. At the first visit, all three cases showed a significantly increased white blood cell count [(27.68–32.02)×109/mL] and a significantly increased erythrocyte sedimentation rate (113–134 mm/h). The C-reactive protein level was significantly increased in two cases (67 mg/L, 147.7 mg/L) and normal in one case. The procalcitonin level was normal in 1 case, elevated in 1 case, and undetected in 1 case. S. pyogenes isolated from cases 1 and 2 were emm1/ST28 and from case 3 was emm12/ST36. All patients were treated by abscess incision and drainage, and S. pyogenes was cultured in the abscess puncture fluid. All patients were treated with intravenous antibiotics after admission, and all patients were cured and discharged. The patients were followed up for 2 months, and their condition was improved and stable. No sequelae such as heart and kidney damage were detected. In conclusion, for children with septic arthritis, early diagnosis and timely treatment with incision and drainage followed by culture of the abscess puncture fluid are important. Once S. pyogenes infection is confirmed, β-lactam antibiotics provide effective treatment, avoiding use of broad-spectrum antibiotics.

Abstract Background The effect of SARS-CoV-2 on existing respiratory pathogens in circulation remains uncertain. This study aimed to assess the impact of SARS-CoV-2 on the prevalence of respiratory pathogens among hospitalized children. Methods This study enrolled hospitalized children with acute respiratory infections in Shenzhen Children’s Hospital from September to December 2019 (before the COVID-19 epidemic) and those from September to December 2020 (during the COVID-19 epidemic). Nasopharyngeal swabs were collected, and respiratory pathogens were detected using multiplex PCR. The absolute case number and detection rates of 11 pathogens were collected and analyzed. Results A total of 5696 children with respiratory tract infection received multiplex PCR examination for respiratory pathogens: 2298 from September to December 2019 and 3398 from September to December 2020. At least one pathogen was detected in 1850 (80.5%) patients in 2019, and in 2380 (70.0%) patients in 2020; the detection rate in 2020 was significantly lower than that in 2019.The Influenza A (InfA) detection rate was 5.6% in 2019, but 0% in 2020. The detection rates of Mycoplasma pneumoniae, Human adenovirus, and Human rhinovirus also decreased from 20% (460), 8.9% (206), and 41.8% (961) in 2019 to 1.0% (37), 2.1% (77), and 25.6% (873) in 2020, respectively. In contrast, the detection rates of Human respiratory syncytial virus, Human parainfluenza virus, and Human metapneumovirus increased from 6.6% (153), 9.9% (229), and 0.5% (12) in 2019 to 25.6% (873), 15.5% (530), and 7.2% (247) in 2020, respectively (p

ABSTRACT Importance The Coronavirus disease 2019 (COVID‐19) global pandemic poses a considerable challenge for pediatricians. Objective This study aimed to identify the epidemiological characteristics and clinical features of pediatric patients with COVID‐19 in China. Methods This multicenter retrospective study included pediatric patients from 46 hospitals in China, covering 12 provinces and two municipalities. Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were analyzed. Results In total, 211 pediatric patients with COVID‐19 were included in this study. The median age was 7.0 years (range: 22 days to 18 years). Approximately 16.3% of the patients exhibited asymptomatic infections, 23.0% had upper respiratory tract infections, and 60.7% had pneumonia, including two with severe pneumonia and one with critical illness. Approximately 78.7% of the pediatric patients occurred in familial clusters. The most three common symptoms or signs at onset in children with COVID‐19 were fever (54.5%), cough (49.3%), and pharyngeal congestion (20.8%). Only 17.6% of the patients presented with decreased lymphocyte count, whereas 13.6% had increased lymphocyte count. Among the patients with pneumonia who exhibited abnormal chest computed tomography findings, 18.2% (23/127) of the patients had no other symptoms. Generally, the chest radiographs showed abnormalities that affected both lungs (49.6%); ground‐glass opacity (47.2%) was the most common manifestation. The cure and improvement rates were 86.7% (183/211) and 13.3% (28/211), respectively. Only one patient with an underlying condition received invasive mechanical ventilation; none of the patients died. Interpretation Similar to adults, children of all age groups are susceptible to COVID‐19. Fortunately, most pediatric patients have mild symptoms or remain asymptomatic, despite the high incidence of pneumonia. Decreased proportions of white blood cells and lymphocytes are less frequent in children than in adults.

Children are at high risk for influenza A virus (IAV) infections, which can develop into severe illnesses. However, little is known about interactions between the microbiome and respiratory tract metabolites and their impact on the development of IAV pneumonia in children. Using a combination of liquid chromatography tandem mass spectrometry (LC-MS/MS) and 16S rRNA gene sequencing, we analyzed the composition and metabolic profile of the oropharyngeal microbiota in 49 pediatric patients with IAV pneumonia and 42 age-matched healthy children. The results indicate that compared to healthy children, children with IAV pneumonia exhibited significant changes in the oropharyngeal macrobiotic structure (p = 0.001), and significantly lower microbial abundance and diversity (p < 0.05). These changes came with significant disturbances in the levels of oropharyngeal metabolites. Intergroup differences were observed in 204 metabolites mapped to 36 metabolic pathways. Significantly higher levels of sphingolipid (sphinganine and phytosphingosine) and propanoate (propionic acid and succinic acid) metabolism were observed in patients with IAV pneumonia than in healthy controls. Using Spearman’s rank-correlation analysis, correlations between IAV pneumonia-associated discriminatory microbial genera and metabolites were evaluated. The results indicate significant correlations and consistency in variation trends between Streptococcus and three sphingolipid metabolites (phytosphingosine, sphinganine, and sphingosine). Besides these three sphingolipid metabolites, the sphinganine-to-sphingosine ratio and the joint analysis of the three metabolites indicated remarkable diagnostic efficacy in children with IAV pneumonia. This study confirmed significant changes in the characteristics and metabolic profile of the oropharyngeal microbiome in pediatric patients with IAV pneumonia, with high synergy between the two factors. Oropharyngeal sphingolipid metabolites may serve as potential diagnostic biomarkers of IAV pneumonia in children.

Objectives The reports on evaluating the classification of antibiotic agents prescribed for Chinese children by combining WHO’s and China’s administrative categories were rare. This study aimed to investigate the pattern of antimicrobial agents prescribing for Chinese children in 2016.Settings 18 tertiary centres from nine provinces located in northern, southern, eastern and western China.Participants The antimicrobial prescribing data from the children admitted in medical wards, surgical wards and intensive care units were collected and analysed. A total of 3680 antibiotic prescriptions for Chinese children were included in the analysis.Primary and secondary outcome measures One-day point-prevalence surveys (PPSs) on antimicrobial prescribing were conducted among hospitalised children in China between 1 February 2016 and 28 February 2017. Five hospitals participated in the first PPS, 13 hospitals in the second PPS, 17 hospitals in the third PPS and 18 hospitals in the fourth PPS. Patterns of antibiotic use with a drug utilisation of 90%, Anatomical Therapeutical Chemical Classification, WHO Access, Watch and Reserve (AWaRe) (version 2019) and antibiotic classification in China were described retrospectively.Results A total of 4442 children and 3680 antibiotic prescriptions for Chinese children were included in the analysis. 2900 (65.3%) children received at least one ongoing antibiotic during the survey days. On the basis of WHO AWaRe classification, the proportion of antibiotics in the Watch group was 76.5% (2814/3680). According to the Management of Antibiotic Classification in China, 56.8% (2089/3680) and 16.1% (594/3680) of antibiotic prescriptions in the Restricted group and the Special group, respectively, were included into broad-spectrum antibiotics. The most common indication for antibiotics was bacterial lower respiratory tract infection (2044/3680, 55.5%).Conclusions The use of broad-spectrum antibiotics was frequent and excessive in hospitalised children in China in 2016.

ObjectivesUse of Broad-spectrum antibiotics is related closely to increasing antimicrobial resistance. Reports on antibiotic prescriptions for Chinese children were rare. We described the prescribing patterns of antibiotic prescriptions for Chinese children from 2017 to 2019 based on the Anatomical Therapeutic Chemical Classification (ATC classification); the Access, Watch, and Reserve (AWaRe) classification from the World Health Organization (WHO), and the Management of Antibiotic Classification in China.MethodsA 1-day point-prevalence survey (PPSs) on antibiotics prescribing for Chinese children was conducted in hospitalized children from 17 centers in 10 Chinese provinces from 1 September 2017 to 30 November 2019.ResultsA total of 4,982 antibiotic prescriptions for Chinese children were included in the analysis. There were 76 types of antibiotic agents in total, 22 (28.9%) of which accounted for 90% of all antibiotic prescriptions. The top-three antibiotics prescribed for children were azithromycin (684, 13.7%), ceftriaxone (508, 10.2%) and latamoxef (403, 8.1%). Third-generation cephalosporins (1,913, 38.4%) were the most commonly prescribed antibiotic classes. On the basis of the AWaRe classification, the Watch group antibiotics accounted for 76.3% and Access group antibiotics accounted for 12.1% of all antibiotic prescriptions. On the basis of the China classification, we showed that 26.5% of antibiotic prescriptions were in the Unrestricted group, 53.6% in the Restricted group, and 14.5% in the Special group.ConclusionThe proportion of antibiotics included in the Watch group and the Special group was high in children in China. The AWaRe classification and China classification for antibiotic prescriptions could be used to supply detailed data for antibiotic stewardship as a simple metric.

Abstract Background Knowledge on the etiology of LRTIs is essential for improvement of the clinical diagnosis and accurate treatment. Molecular detection methods were applied to identify a broad range of bacterial and viral pathogens in a large set of bronchial alveolar lavage (BAL) fluid samples. The patterns of detected pathogens were correlated to the clinical symptoms. Methods BAL fluid samples and clinical data were collected from 573 hospitalized children between 1 month and 14 years of age with LRTIs, enrolled from January to December 2018. Pathogens were detected using standardized clinical diagnostics, with a sensitive, high-throughput GeXP-based multiplex PCR and with multiplex qPCR. Data were analyzed to describe the correlation between the severity of respiratory tract disease and the pathogens identified. Results The pathogen detection rate with GeXP-based PCR and multiplex qPCR was significantly higher than by clinical routine diagnostics (76.09% VS 36.13%,χ2 = 8.191, P = 0.004). The most frequently detected pathogens in the BAL fluid were human adenovirus (HADV)(21.82%), Mycoplasma pneumoniae (20.24%), human rhinovirus (13.96%), Streptococcus pneumoniae (8.90%) and Haemophilus influenzae (8.90%). In 16.4% of the cases co-detection with two or three different pathogens was found. Viral detection rates declined with age, while atypical pathogen detection rates increased with age. Oxygen supply in the HADV and Influenza H1N1 infected patients was more frequent (49.43%) than in patients infected with other pathogens. Conclusion Broad range detection of viral and bacterial pathogens using molecular methods is a promising and implementable approach to improve clinical diagnosis and accurate treatment of LRTI in children.

ABSTRACT Mycoplasma pneumoniae is a common pathogen causing respiratory disease in children. We sought to investigate the epidemiology of M. pneumoniae among outpatient children with mild respiratory tract infections (RTIs) during the coronavirus disease 2019 (COVID-19) pandemic. Eligible patients were prospectively enrolled from January 2020 to June 2021. Throat swabs were tested for M. pneumoniae RNA. M. pneumoniae IgM was tested by a colloidal gold assay. Macrolide resistance and the effect of the COVID-19 countermeasures on M. pneumoniae prevalence were assessed. Symptom scores, treatments, and outcomes were evaluated. Eight hundred sixty-two eligible children at 15 centers in China were enrolled. M. pneumoniae was detected in 78 (9.0%) patients. Seasonally, M. pneumoniae peaked in the first spring and dropped dramatically to extremely low levels over time until the next summer. Decreases in COVID-19 prevalence were significantly associated with decreases in M. pneumoniae prevalence (r = 0.76, P = 0.001). The macrolide resistance rate was 7.7%. The overall sensitivity and specificity of the colloidal gold assay used in determining M. pneumoniae infection were 32.1% and 77.9%, respectively. No more benefits for improving the severity of symptoms and outcomes were observed in M. pneumoniae-infected patients treated with a macrolide than in those not treated with a macrolide during follow-up. The prevalences of M. pneumoniae and macrolide resistance in outpatient children with mild RTIs were at low levels in the early stage of the COVID-19 pandemic but may have rebounded recently. The colloidal gold assay for M. pneumoniae IgM may be not appropriate for diagnosis of M. pneumoniae infection. Macrolides should be used with caution among outpatients with mild RTIs. IMPORTANCE This is the first and largest prospective, multicenter, active, population-based surveillance study of the epidemiology of Mycoplasma pneumoniae among outpatient children with mild respiratory tract infections (RTIs) during the COVID-19 pandemic. Nationwide measures like strict face mask wearing and restrictions on population movement implemented to prevent the spread of COVID-19 might also effectively prevent the spread of M. pneumoniae. The prevalence of M. pneumoniae and the proportion of drug-resistant M. pneumoniae isolates in outpatient children with mild RTIs were at low levels in the early stage of the COVID-19 pandemic but may have rebounded recently. The colloidal gold assay for M. pneumoniae IgM may be not appropriate for screening and diagnosis of M. pneumoniae infection. Macrolides should be used with caution among outpatients with mild RTIs.

Streptococcus pyogenes is a bacterial pathogen that causes a wide spectrum of clinical diseases exclusively in humans. The distribution of emm type, antibiotic resistance and virulence gene expression for S. pyogenes varies temporally and geographically, resulting in distinct disease spectra. In this study, we analyzed antibiotic resistance and resistance gene expression patterns among S. pyogenes isolates from pediatric patients in China and investigated the relationship between virulence gene expression, emm type, and disease categories. Forty-two representative emm1.0 and emm12.0 strains (n = 20 and n = 22, respectively) isolated from patients with scarlet fever or obstructive sleep apnea-hypopnea syndrome were subjected to whole-genome sequencing and phylogenetic analysis. These strains were further analyzed for susceptibility to vancomycin. We found a high rate and degree of resistance to macrolides and tetracycline in these strains, which mainly expressed ermB and tetM. The disease category correlated with emm type but not superantigens. The distribution of vanuG and virulence genes were associated with emm type. Previously reported important prophages, such as φHKU16.vir, φHKU488.vir, Φ5005.1, Φ5005.2, and Φ5005.3 encoding streptococcal toxin, and integrative conjugative elements (ICEs) such as ICE-emm12 and ICE-HKU397 encoding macrolide and tetracycline resistance were found present amongst emm1 or emm12 clones from Shenzhen, China.

Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies.Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses.Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus. Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively.Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis.

BackgroundThe pandemic of Coronavirus Disease 2019 (COVID-19) brings new challenges for pediatricians, especially in the differentiation with non-COVID-19 pneumonia in the peak season of pneumonia. We aimed to compare the clinical characteristics of pediatric patients with COVID-19 and other respiratory pathogens infected pneumonias.MethodsWe conducted a multi-center, cross-sectional study of pediatric inpatients in China. Based on pathogenic test results, pediatric patients were divided into three groups, including COVID-19 pneumonia group, Non-COVID-19 viral (NCV) pneumonia group and Non-viral (NV) pneumonia group. Their clinical characteristics were compared by Kruskal-Wallis H test or chi-square test.ResultsA total of 636 pediatric pneumonia inpatients, among which 87 in COVID-19 group, 194 in NCV group, and 355 in NV group, were included in analysis. Compared with NCV and NV patients, COVID-19 patients were older (median age 6.33, IQR 2.00-12.00 years), and relatively fewer COVID-19 patients presented fever (63.2%), cough (60.9%), shortness of breath (1.1%), and abnormal pulmonary auscultation (18.4%). The results were verified by the comparison of COVID-19, respiratory syncytial virus (RSV) and influenza A (IFA) pneumonia patients. Approximately 42.5%, 44.8%, and 12.6% of the COVID-19 patients presented simply ground-glass opacity (GGO), simply consolidation, and the both changes on computed tomography (CT) scans, respectively; the proportions were similar as those in NCV and NV group (p>0.05). Only 47.1% of COVID-19 patients had both lungs pneumonia, which was significantly lower than that proportion of nearly 80% in the other two groups. COVID-19 patients presented lower proportions of increased white blood cell count (16.5%) and abnormal procalcitonin (PCT) (10.7%), and a higher proportion of decreased lymphocyte count (44.0%) compared with the other two groups.ConclusionMajority clinical characteristics of pediatric COVID-19 pneumonia patients were milder than non-COVID-19 patients. However, lymphocytopenia remained a prominent feature of COVID-19 pediatric pneumonia.

Pneumonia is one of the most important causes of morbidity and mortality in children. Identification and characterization of pathogens that cause infections are crucial for accurate treatment and accelerated recovery. However, in most cases, the causative agent cannot be identified, which is partly due to the limited spectrum of pathogens covered by current diagnostics based on nucleic acid amplification. Therefore, in this study, we explored the application of metagenomic next-generation sequencing (mNGS) for the diagnosis of children with severe pneumonia. From April to July 2017, 32 hospitalized children with severe nonresponding pneumonia in Shenzhen Children's Hospital were included in this study. Blood tests were conducted immediately after hospitalization to assess cell counts and inflammatory markers, oropharyngeal swabs were collected to identify common pathogens by qPCR and culture. After bronchoscopy, bronchoalveolar lavage fluid (BALF) samples were collected for further pathogen identification using standardized diagnostic tests and mNGS. Blood tests were normal in 3 of the 32 children. In 9 oropharyngeal swabs, bacterial pathogens were detected, in 5 of these Mycoplasma pneumoniae was detected. Adenovirus was detected in 5 BALF samples, using the Direct Immunofluorescence Assay (DFA). In 15 cases, no common pathogens were found in BALF samples, using the current standard diagnostic tests, while in all 32 BALFs, pathogens were identified using mNGS, including adenovirus, Mycoplasma pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, cytomegalovirus and bocavirus. This study shows that, with mNGS, the sensitivity of detection of the causative pathogens in children with severe nonresponding pneumonia is significantly improved. In addition, mNGS gives more strain specific information, helps to identify new pathogens and could potentially help to trace and control outbreaks. In this study, we have shown that it is possible to have the results within 24 hours, making the application of mNGS feasible for clinical diagnostics.

Abstract Importance A cluster of influenza‐associated deaths occurred among children during pandemic 2009 influenza A (H1N1) in China, but the risk factors and causes for death have not been clarified. Objective We describe the clinical findings regarding 2009 influenza A (H1N1)‐associated pediatric deaths in China, including the risk factors for death. Methods The definition of 2009 influenza A (H1N1)‐associated pediatric death is death in a child who is younger than 14 years and has laboratory‐confirmed influenza. We collected data of total 810 hospitalized patients with 2009 influenza A (H1N1) infection from September 2009 to February 2010 in 17 hospitals across China. The clinical characteristics, laboratory abnormalities, and treatment course were retrospectively studied. Results Of the 810 patients hospitalized with 2009 influenza A (H1N1) infection, 19 (2.3%) died. Ten patients died from severe pneumonia and acute respiratory distress syndrome; eight died from encephalopathy/encephalitis; one died from secondary fungal meningitis. Patients who died were more likely than patients who survived to have neutrophilia, lymphopenia, elevated C‐reactive protein, and elevations of lactate dehydrogenase, creatine kinase, creatine kinase‐MB, aspartate aminotransferase and alanine aminotransferase. There were no significant differences in the median age, median time from onset of illness to admission, underlying chronic disease, and initiation of antiviral therapy within 48 hours of illness onset, between patients who died and those who survived. Interpretation The risk factors for pediatric death associated with 2009 influenza A (H1N1) infection are different from those of seasonal influenza. The most common causes of death are viral pneumonia, acute respiratory distress syndrome, and encephalopathy/encephalitis.

Community-acquired pneumonia (CAP) is a worldwide infectious disease caused by bacteria, viruses, or a combination of these infectious agents. Mycoplasma pneumoniae is an atypical pneumonia pathogen that causes high morbidity and mortality in children, and adenovirus can lead to severe pneumonia. However, the etiology of different types of pneumonia is still unclear. In this study, we selected a total of 52 inpatients with M. pneumoniae pneumonia (MPP) (n = 21), adenovirus pneumonia (AVP) (n = 16), or tracheomalacia (n = 15) to serve as a disease control. Bronchoalveolar lavage fluid (BALF) samples that had been obtained for clinical use were analyzed. We compared the differences in microbiota and the expression of 10 inflammatory cytokines in samples between MPP, AVP, and tracheomalacia. We found that the bacterial diversity in MPP was lower than that in AVP and tracheomalacia. Mycoplasma, Streptococcus, and Pseudomonas were predominant in samples of MPP, AVP, and tracheomalacia, respectively. The expression levels of IL-6, IL-8, and IL-10 were significantly higher in inpatients with AVP compared to children hospitalized with tracheomalacia or MPP. The lung microbiota in MPP was remarkably correlated with IL-2, IL-4, IL-5, IL-6, TNF-α, and IL-1α expressions, while this was not found in tracheomalacia and AVP. Microbiota analysis identified a high load of multi-drug resistant Acinetobacter baumannii in the lung microbiota of several inpatients, which might be associated with the long hospitalization length and intra-group differences at the individual level. This study will help to understand the microbial etiology of tracheomalacia, AVP, and MPP and to identify effective therapies for these diseases.

Background: Group B Streptococcus (GBS) is an important neonatal pathogen associated with high morbidity and mortality in developed countries. However, data describing neonatal GBS disease in developing countries, particularly in Asia, are largely incomplete. The aim of this study was to determine the serotype distribution, antimicrobial resistance, and molecular characteristics of invasive GBS isolates recovered from Chinese neonates. Methods: From 2008 to 2013, 40 GBS isolates were recovered from infected neonates less than 3 months of age. All isolates were identified with the CAMP test and commercially available techniques. Serotyping was performed by latex agglutination. Antibiotic susceptibility was tested with Etest strips and the disk diffusion method. Multilocus sequence typing and erythromycin resistance gene detection (ermB and mefA) were performed by PCR. Results: Four serotypes were identified. Serotype III (85%) was the most prevalent, followed by Ia (7.5%), Ib (5%), and V (2.5%). All isolates were sensitive to penicillin, ceftriaxone, and levofloxacin. However, resistance to erythromycin (92.5%), clindamycin (87.5%), and tetracycline (100%) was observed. Among erythromycin-resistant isolates, 73.0% carried the ermB gene alone, 5.4% carried the mefA gene alone, and 21.6% expressed both ermB and mefA genes. A total of seven sequence types (STs) were identified; the most prevalent was ST17, accounting for 80% of all isolates. Further, serotype III isolates contained ST17 (94.2%), ST19 (2.9%), and ST650 (2.9%). Conclusion: Serotype distribution, antimicrobial susceptibility, and sequence type characterization in Asia and in other global regions may contribute to improve the prevention and treatment of neonatal GBS infections.

UNLABELLED:Diffuse parenchymal lung diseases in children (chDPLD) or interstitial lung diseases in children (chILD) represent a heterogeneous group of respiratory disorders that are mostly chronic and associated with high morbidity and mortality. However, the incidence of chDPLD is so low that most pediatricians lack sufficient knowledge of chDPLD, especially in China. Based on the clinico-radiologic-pathologic (CRP) diagnosis, we tried to describe (1) the characteristics of chDPLD and (2) the ratio of each constituent of chDPLD in China. Data were evaluated, including clinical, radiographic, and pathologic results from lung biopsies. We collected 25 cases of chDPLD, 18 boys and 7 girls with a median age of 6.0 years, from 16 hospitals in China. The most common manifestations included cough (n = 24), dyspnea (n = 21), and fever (n = 4). There were three cases of exposure-related interstitial lung disease (ILD), three cases of systemic disease-associated ILD, nineteen cases of alveolar structure disorder-associated ILD, and no cases of ILD specific to infancy. Non-specific interstitial pneumonia (n = 9) was the two largest groups. CONCLUSION:Non-specific interstitial pneumonia is the main categories of chDPLD in China. Lung biopsy is always a crucial step in the final diagnosis. However, clinical and imaging studies should be carefully evaluated for their value in indicating a specific chDPLD.

OBJECTIVE: To provide guidance for clinical disease prevention and treatment, this study examined the epidemiology, antibiotic susceptibility, and serotype distribution of Streptococcus pneumoniae (S. pneumoniae) associated with invasive pneumococcal diseases (IPDs) among children less than 14 years of age in Shenzhen, China. MATERIALS AND METHODS: All the clinical strains were isolated from children less than 14 years old from January 2009 to August 2012. The serotypes and antibiotic resistance of strains of S. pneumoniae were determined using the capsular swelling method and the E-test. RESULTS: A total of 89 strains were isolated and 87 isolates were included. The five prevailing serotypes were 19F (28.7%), 14 (16.1%), 23F (11.5%), 19A (9.2%) and 6B (6.9%). The most common sequence types (ST) were ST271 (21.8%), ST876 (18.4%), ST320 (8.0%) and ST81 (6.9%) which were mainly related to 19F, 14, 19A and 23F, respectively. The potential coverage by 7-, 10-, and 13-valent pneumococcal conjugate vaccine were 77.0%, 77.0%, and 89.7%, respectively. Among the 87 isolates investigated, 11.5% were resistant to penicillin, and for meningitis isolates, the resistance rate was 100%. Multi-drug resistance (MDR) was exhibited by 49 (56.3%) isolates. Eighty-four isolates were resistance to erythromycin, among which, 56 (66.7%) carried the ermB gene alone and 28 (33.3%) expressed both the ermB and mefA/E genes. CONCLUSIONS: The potential coverage of PCV13 is higher than PCV7 and PCV10 because high rates of serotypes 19A and 6A in Shenzhen. The clinical treatment of IPD needs a higher drug concentration of antibiotics. Continued surveillance of the antimicrobial susceptibility and serotypes distribution of IPD isolates may be necessary.

Detailed molecular analyses of Clonal Complex 59 (CC59) methicillin-resistant Staphylococcus aureus (MRSA) isolates from children in seven major cities across Mainland China were examined. A total of 110 CC59 isolates from invasive and non-invasive diseases were analyzed by multilocus sequence typing (MLST), Staphylococcus cassette chromosome mec (SCCmec) typing, staphylococcal protein A (spa) typing and pulsed-field gel electrophoresis (PFGE). Antibiotics susceptibilities, carriage of plasmids and 42 virulence genes and the expression of virulence factors were examined. ST59 (101/110, 91.8%) was the predominant sequence type (ST), while single locus variants (SLVs) belonging to ST338 (8/110, 7.3%) and ST375 (1/110, 0.9%) were obtained. Three SCCmec types were found, namely type III (2.7%), type IV (74.5%) and type V (22.7%). Seven spa types including t437, which accounted for 87.3%, were determined. Thirteen PFGE types were obtained. PFGE types A and B were the major types totally accounting for 81.8%. The dominant clone was ST59-t437-IVa (65.5%), followed by ST59-t437-V (14.5%). The positive rate of luks-PV and lukF-PV PVL encoding (pvl) gene was 55.5%. Plasmids were detected in 83.6% (92/110) of the strains. The plasmid size ranging from 23.4 kb to 50 kb was most prevalent which accounted for 83.7% (77/92). A significantly lower expression of hla was found in ST59-t437-IVa compared with ST59-t437-V. Among the 110 cases, 61.8% of the patients were less than 1 year old. A total of 90 cases (81.8%) were community-associated (CA) infections whereas 20 cases (18.2%) were hospital-associated (HA) infections. Out of the 110 patients, 36.4% (40/110) were diagnosed with invasive infectious diseases in which ST59-t437-IVa accounted for 67.5% (27/40). In brief, ST59-t437-IVa was proved as the dominant clone in CC59 MRSA strains. The carriage rate of pvl gene was high. CC59 MRSA could result in CA and HA infections. The majortiy of MRSA infection children were in young age.

With the widespread use of antibiotics, antimicrobial resistance (AMR) has become a global problem that endangers public health. Despite the global high prevalence of group A Streptococcus (GAS) infections and the global widespread use of b-lactams, b-lactams remain the first-line treatment option for GAS infection. b-hemolytic streptococci maintain a persistent susceptibility to b-lactams, which is an extremely special phenomenon in the genus Streptococci, while the exact current mechanism is not known. In recent years, several studies have found that the gene encoding penicillin binding protein 2X (pbp2x) is associated with GAS with reduced-b-lactam susceptibility. The purpose of this review is to summarize the current published data on GAS penicillin binding proteins and b-lactam susceptibility, to explore the relationship between them, and to be alert to the emergence of GAS with reduced susceptibility to b-lactams. [ABSTRACT FROM AUTHOR]